Fluometuron Registration Review Human Health Assessment Scoping Document 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

D430248 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 02-MAR-2016 

SUBJECT: Fluometuron. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 035503 DP Barcodes: 0430248; D391415 

Decision No.: 511228 Registration No.: NIA 

Petition No.: NIA Regulatory Action: Registration Review Scoping Document 

Risk Assessment Type: NIA Case No.: 0040 

TXR No.: NIA CAS No.: 2164-17-2 

MRID No.: 48491201 40 CFR: §180.229 

FROM: 

I . Julie 

Shalu 

Van 

Shelat

Alstine

, Environmental 

, Environmental 

Healtty.Scienti§.l: 

Health Scientist

~Q~ 

~ 

\.• o _ 

Nancy McCarroll, Toxicologist ~~IA c~ 

Risk Assessment Branch VI (RABVI) 

Health Effects Division (HED, 7509P) 

THROUGH: Donna Davis, Acting Branch Chief 

RABVl /HED (7509P) 

TO: Kelly Sherman, Tracy Perry, and Linsey Walsh 

Risk Management & Implementation Branch 3 

Pesticide Re-Evaluation Division (PRD; 7508P) 

Attached is HED's human health risk assessment scoping document for fluometuron to support 

Registration Review. 

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Table of Contents

Executive Summary ........................................................................................................................ 3

1.0 Introduction .............................................................................................................................. 4

2.0 Hazard Characterization/Assessment ....................................................................................... 4

3.0 Residue Chemistry ................................................................................................................... 5

4.0 Dietary Exposure ..................................................................................................................... 7

5.0 Residential Exposure ............................................................................................................... 8

6.0 Non-occupational and Bystander Exposure .............................................................................. 8

7.0 Aggregate Risk Assessment ..................................................................................................... 8

8.0 Occupational Exposure ............................................................................................................ 9

9.0 Public Health and Pesticide Epidemiology Data ................................................................... 10

10.0 Tolerance Assessment and International Harmonization .................................................... 11

11.0 Environmental Justice .......................................................................................................... 11

12.0 Cumulative ........................................................................................................................... 11

13.0 Human Studies ..................................................................................................................... 12

14.0 Risk Assessment Updates and Data Deficiencies ................................................................ 12

15.0 References ............................................................................................................................ 13

16.0 Attachments .......................................................................................................................... 13

Attachment 1: Chemical Identity Tables. .................................................................................... 15

Attachment 2: Fluometuron Acute, Subchronic, and Chronic Toxicity Profile. ......................... 19

Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (From 2005 

Risk Assessment). ......................................................................................................................... 24

Attachment 4: Summary of Registered Uses for Fluometuron. ................................................... 26

Attachment 5: DFR Waiver Criteria. ........................................................................................... 27

Attachment 6: Fluometuron International Residue Limit Status Sheet. ...................................... 28

Attachment 7. Bovine Liver and Milk Hydroxylated Metabolite Storage Stability Data ........... 29

Attachment 8. Status of Chemistry Deficiencies Identified During Reregistration ..................... 31

Attachment 9. Submittal of Analytical Reference Standards (860.1650) .................................... 33

 

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Executive Summary 

HED has prepared a scoping document to support Registration Review of the herbicide 

fluometuron [N,N-dimethyl-N’-(3-(trifluoromethyl)phenyl)urea]. Fluometuron is a preplant, 

preemergence, and/or postemergence phenylurea herbicide for the selective control of broadleaf 

weeds and annual grasses. In addition to a Section 3 use on cotton, fluometuron is registered as a 

Special Local Needs (SLN) use on wildflowers in North Carolina (EPA Reg No. NC 120002). 

Products containing fluometuron are formulated as soluble concentrates (SC) and liquids (L), 

and may be applied as broadcast, band, over-the-top spray, semi-directed, directed, preplant, 

preemergence, postemergence, or layby treatments. The most recent human health risk 

assessment for fluometuron was performed in 2005 entitled “Fluometuron: Revised HED Risk 

Assessment for Phase III of the Reregistration Eligibility Decision (RED)” (E. Reaves, D341152, 

2/1/2005). 

HED has evaluated the status of the human health assessments for fluometuron to determine 

whether sufficient data are available, and whether any updates are needed to support Registration 

Review. HED has considered all available data and human health risk assessments for 

fluometuron with respect to its toxicity, exposure, and usage databases, and the most updated 

Agency science policy and risk assessment methodologies to determine the scope of work 

necessary to support Registration Review. 

The toxicology database for fluometuron is complete and adequate to support Registration 

Review. No additional data are required. As part of Registration Review, the endpoints, doses, 

and safety factors used in the most recent risk assessment will be re-evaluated according to 

current HED policy. 

The residue chemistry database is sufficient to support the current registrations. No additional 

residue chemistry data are required; however, analytical standards for the fluometuron 

metabolites are not available at this time and should be submitted. Additionally, one label 

contains a gin trash livestock feeding restriction that should be removed (EPA Reg. No. 66330-

260). Fluometuron is registered for use on cotton and tolerances are established for residues of 

fluometuron in cotton and livestock commodities. Cereal grains, peanuts, rice, and soybeans are 

registered as rotational crops and inadvertent tolerances are established for residues of 

fluometuron in these commodities. There are no Codex or Canadian maximum residue limits 

(MRLs) established for residues of fluometuron; therefore, harmonization is not an issue at this 

time. The tolerance expressions in 40 CFR§180.229 have not been updated to reflect current 

HED policies and will need to be revised during Registration Review. 

The most recent acute and chronic dietary risk estimates were below HED’s level of concern for 

the general U.S. population and all population subgroups examined. The most recent cancer 

dietary (food and water) risk estimate was 1.24 x 10-5. Drinking water was a driver in the cancer 

assessment. As part of Registration Review, updated acute, chronic, and cancer dietary exposure 

and risk assessments may be required. These assessments should incorporate updated percent crop 

treated (PCT) data (including percent crop rotated data), monitoring data (if available), updated 

estimated drinking water concentrations (EDWCs) from EFED, the most recent dietary exposure 

assessment model, and any revised toxicological points of departure (PODs). 

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There are no proposed or current registrations for products containing fluometuron that allow 

residential use. Therefore, residential handler and post-application exposure assessments will 

not be needed during Registration Review. 

The need for spray drift and volatilization risk assessments for fluometuron will be examined 

during Registration Review. 

In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate 

(add) pesticide exposures and risks from three major sources: food, drinking water, and 

residential exposures. Because there are no residential uses for fluometuron, only food and water 

were included in previous aggregate assessments. There is sufficient information available to 

assess aggregate exposure; however, a new aggregate risk assessment may be required during 

Registration Review if the dietary exposure analyses are updated to reflect revised PCT data, 

monitoring data, EDWCs, or a new dietary exposure assessment model, and/or the PODs are 

revised. 

The occupational exposure database is adequate to support the Registration Review process for 

fluometuron. The most recent occupational handler and post-application exposure assessments 

are not reflective of current exposure policies and data, but did not identify risks of concern 

(MOEs ≥ 100). During Registration Review, updated occupational handler dermal and 

inhalation assessments may be conducted to reflect all currently registered uses and maximum 

application rates, using current occupational and residential exposure (ORE) policies and 

updated toxicological PODs. Additionally, the SLN label (NC 120002) should be updated to 

indicate that a respirator is required when fluometuron is applied with a mechanically 

pressurized handgun. 

1.0 Introduction 

Fluometuron is a preplant, preemergence, and/or postemergence phenylurea herbicide for the 

selective control of broadleaf weeds and annual grasses. In addition to the Section 3 use on 

cotton, fluometuron is registered as a SLN use on wildflowers in North Carolina (EPA Reg No. 

NC 120002). HED has reviewed the most recent exposure and risk assessments for fluometuron, 

as well as toxicity data, exposure and usage databases, and the latest Agency science policy and 

risk assessment methodologies to determine if sufficient data are available and if updates are 

needed to support Registration Review. 

2.0 Hazard Characterization/Assessment 

When the RED was released in 2005, the toxicology database was considered adequate to 

characterize the toxicity of fluometuron. Since that time, however, the Toxicology Data 

Requirements have been revised (40 CFR Part 158 Toxicology Data Requirements, 2007) and 

now include an immunotoxicity study, a subchronic inhalation toxicity study, and acute and 

subchronic neurotoxicity studies. None of these studies are available for fluometuron. In 2013, 

the Hazard and Science Policy Council (HASPOC) reviewed the databases of the phenylurea 

herbicides, which includes fluometuron, and concluded that immunotoxicity study data waivers 

could be granted for this chemical class (Habiba, 2013; TXR No. 0056795). Additionally, based 

on a weight-of-evidence (WOE) approach, the HASPOC granted a data waiver for the 

subchronic inhalation test, with the provision that a respirator is used to protect workers when 

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fluometuron is applied to wildflowers in NC (SLN use) with a mechanically pressurized 

handgun. Similarly, data waivers were granted for both the acute and subchronic neurotoxicity 

studies (Habiba, 2015, TXR No. 0057314). 

Fluometron is slightly toxic in acute oral, dermal, and inhalation studies (Toxicity Category III). 

It is moderately toxic in primary eye and dermal irritation studies (Toxicity Category II). It is 

not, however, a dermal sensitizer. 

Fluometuron induces lung adenomas and carcinomas in male mice and malignant lymphocytic 

lymphomas in female mice. It is classified as a Group C – possible human carcinogen and for 

the purposes of the risk characterization, both a low dose extrapolation model (Q1

*

) was applied 

to the animal data (lung tumors in male mice) and the Reference Dose (RfD) approach was used. 

The unit risk, Q1

*

 (mg/kg/day)-1 is 1.80 x 10-2 in human equivalents. No compound related 

tumors were observed in the rats and genotoxicity studies with fluometuron were negative. 

In other toxicology studies, the spleen, kidney, and liver appear to be the organs consistently 

affected following exposure to moderate doses of fluometuron in rats and dogs in subchronic, 

chronic, developmental, and reproductive studies. Effects in the spleen are consistently linked to 

an increased turnover of red blood cells (RBCs) and the deposition of hemosiderin pigment in 

the breakdown of RBCs; however, no systemic changes were found in male or female rabbits 

exposed dermally to the limit dose. 

Reproductive or developmental effects in rats or rabbits were only observed at maternally toxic 

doses; thus, an increased sensitivity of the young was not associated with this chemical. No 

developmental effects were found in rats or rabbits and no reproductive effects attributable to 

fluometuron were found in male or female rats. 

Fluometuron was rapidly absorbed (within the first 24 hours), distributed to all tissues, and the 

majority of the radiolabel test substance was excreted in the urine within the first 24 hours 

following dosing, with a small percentage (6-12%) found in the feces. Fluometuron is 

metabolized by oxidative processes to yield a variety of ring hydroxylated metabolites. For risk 

characterization, the parent (fluometuron) endpoints are used, and all metabolites of concern are 

calculated as fluometuron equivalents. The metabolism of fluometuron in drinking water 

analysis has been reviewed. The parent fluometuron is very stable to abiotic hydrolysis and 

photolysis in water and on soil. It is also stable to aerobic soil metabolism, anaerobic soil 

metabolism, and anaerobic aquatic metabolism 

Conclusions: The toxicology database for fluometuron is complete and adequate to support 

Registration Review. No additional data are required. As part of Registration Review, the 

endpoints, doses, and safety factors used in the most recent risk assessment (Attachment 2) will 

be re-evaluated according to current HED policy. 

3.0 Residue Chemistry 

The residue chemistry database is sufficient to support the current registrations. The nature of 

the residue in plants and livestock is adequately understood. Acceptable studies depicting the 

qualitative nature of the residue in cotton plants, ruminants, and poultry have been submitted and 

evaluated. The HED Metabolism Committee concluded that for plants, the residues of concern 

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consist of fluometuron and its metabolites determined as trifluoromethyl aniline (TFMA), and 

for meat, milk, poultry, and eggs, the residues of concern consist of fluometuron and its 

metabolites determined as TFMA and the hydroxylated metabolites CGA-236431, CGA-236432, 

CGA-13211, and their conjugates (S. Funk, HED Metabolism Committee Memorandum, 

2/22/1996). A detailed discussion of the nature of the residues, residue analytical methods, 

available field trial and processing data, and rotational crop studies for fluometuron can be found 

in the most recent chemistry chapter (S. Ary, 11/30/2004; D300553). 

Acceptable data collection methods that are capable of determining all fluometuron residues of 

concern in plant (Methods AG-528 and AG-529) and livestock (Methods AG-678; AG-519; AG519A) commodities have been submitted. HED previously requested that the registrant either 

improve Method AG-519A or develop a new method capable of determining fluometuron 

residues that may be converted to TFMA in livestock commodities (S. Ary, 30-NOV-2004; 

D300553). Subsequently, the Registrant submitted a waiver request for a revised Method AG519A, and HED reviewed the supporting rationale and recommended that the study requirement 

be waived (Memo, P. Barnes, 4/23/2009; D300532). The Analytical Chemistry Branch (ACB) 

has reviewed the available method data (without laboratory validation) for Methods 519, 519A, 

AG-678, AG-528, and AG-529 and concluded that the methods appear to meet the 860.1340 

Residue Chemistry Test Guidelines for acceptable tolerance enforcement methods (Memo, C. 

Stafford, 3/13/2009; D300532). The FDA PESTDATA database dated 10/1999 (PAM Volume 

I, Appendix I) indicates that fluometuron is completely recovered using Multiresidue Methods 

Section 403 (method for phenylurea herbicides). 

Adequate storage stability data are available to support the registered uses. HED previously 

requested storage stability data for the hydroxylated metabolites of fluometuron (CGA-236431, 

CGA-236432, CGA-13211) in ruminant milk and muscle (up to 269 days) and egg and poultry 

tissues (approximately 4 months; Memo, S. Ary, 11/30/2004; D300553). Subsequently, the 

ChemSAC recommended that storage stability studies on the hydroxylated metabolites be 

conducted for residues in ruminant liver and milk samples and that any requirement for 

additional poultry data be deferred until the required ruminant storage stability data had been 

submitted and reviewed (ChemSAC Minutes, 17-OCT-2007). ChemSAC also recommended 

that if the ruminant storage stability data indicated that residues were stable, a poultry feeding 

study and storage stability data for egg and poultry tissues would not be required. Acceptable 

storage stability data for bovine liver and milk have been submitted to the Agency (MRID 

48491201) and these deficiencies are now resolved. The results of the study showed that 

residues of the hydroxyfluometuron metabolites CGA-13211, CGA-235431, and CGA-235432 

are stable for at least 12.9 months for liver and 12.0 months for milk when stored at or below -12 

°C (see Attachment 7). Since the ruminant liver and milk data indicated that residues are stable 

for the storage duration, a poultry feeding study and storage stability data for egg and poultry 

tissues are not required at this time. 

Several residue chemistry data requirements were identified as part of Reregistration (E. Reaves, 

2/1/2005; D341152). Aside from one label revision, the chemistry data deficiencies identified as 

part of Reregistration have been adequately addressed (Attachment 8). The Flomet 4L label 

(EPA Reg. No. 66330-260) still contains a gin trash livestock feeding restriction that should be 

removed since cotton gin trash is not under the control of the grower. 

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Analytical reference standards for the parent fluometuron are currently available in EPA’s 

National Pesticide Standards Repository (NPSR) and expire on 6/30/2016. Analytical reference 

standards are currently unavailable in EPA’s NPSR for the following metabolites: 

trifluoromethylaniline (out of stock); CGA-236431 (expired on 6/26/2014); CGA-236432 

(expired on 6/26/2014); and CGA-13211 (expired on 6/26/2014) (Email communication with G. 

Verdin of BEAD/ACB on 11/9/2015). Analytical reference standards should be submitted to the 

NPSR (see Attachment 9 for submission information). 

Conclusions: The residue chemistry database is sufficient to support the current registrations. 

Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the 

residue, and processing data are available to support the registered uses. Adequate methods are 

available for enforcement of the currently established tolerances. No additional residue 

chemistry data are required to support the current registrations; however, analytical standards are 

required for several fluometuron metabolites (Attachment 9). Additionally, the gin trash feeding 

restriction from one label should be removed (EPA Reg. No. 66330-260). 

4.0 Dietary Exposure 

Acute, chronic, and cancer dietary (food and drinking water) assessments were conducted for 

fluometuron to support HED’s Reregistration Eligibility Decision (RED) document (Memo, S. 

Ary, 9/27/2005; D321682). Estimated Drinking Water Concentration (EDWC) values were 

provided by the Environmental Fate and Effects Division (EFED) and were directly incorporated 

into the assessment. The dietary risk assessments incorporated refined PCT data for cotton and 

the estimated percent of rotated crops exposed to fluometuron. These assessments were 

performed using Dietary Exposure Evaluation Model software with the Food Commodity Intake 

Database (DEEM-FCID, Version 2.03), which uses food consumption data from the US 

Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals 

(CSFII) from 1994-1996 and 1998. 

The acute (Monte-Carlo), chronic, and cancer assessments were moderately refined and used 

field trial anticipated residue (AR) data, PCT data, ARs for livestock commodities, and empirical 

and default processing factors. Acute dietary risk estimates were provided for females 13-49 

years old only since there is no study to support an effect from a single dose for the general U.S. 

population. The acute and chronic dietary risk estimates do not exceed HED’s level of concern 

(less than 100% of the PAD). The acute dietary risk at the 99.9th exposure percentile for females 

13-49 years old was 4.5% of the acute population-adjusted dose (aPAD). The chronic dietary 

risk estimates were 13% of the chronic population-adjusted dose (cPAD) for the general U.S. 

population and 41% of the cPAD for all infants less than 1 year old, the most highly-exposed 

population subgroup. The cancer assessment resulted in a fluometuron dietary (food and 

drinking water) exposure estimate of 0.000688 mg/kg/day for the general U.S. population. 

Applying the Q1* of 1.80 x 10-2 (mg/kg/day)-1 to the exposure value resulted in a cancer risk 

estimate of 1.24 x 10-5. The significant cancer risk contributor was identified as water (direct, all 

sources and indirect, all sources). 

Conclusions: The most recent acute and chronic dietary risk estimates were below HED’s level of 

concern for the general U.S. population and all population subgroups examined. The most recent 

cancer dietary (food and water) risk estimate was 1.24 x 10-5. Drinking water was a driver in the 

cancer assessment. As part of Registration Review, updated acute, chronic, and cancer dietary 

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exposure and risk assessments may be required. These assessments should incorporate updated 

PCT data (including percent crop rotated data), monitoring data (if available), updated EDWCs 

from EFED, the most recent version of DEEM-FCID, and any revised toxicological PODs. 

5.0 Residential Exposure 

There are no registered or proposed fluometuron products that allow residential use; therefore, a 

quantitative residential exposure assessment was not conducted. 

Conclusions: There are no proposed or current registrations for products containing fluometuron 

that allow residential use. Therefore, residential handler and post-application exposure 

assessments will not be needed during Registration Review. 

6.0 Non-occupational and Bystander Exposure 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of fluometuron. The potential for spray drift 

will be quantitatively evaluated for each pesticide during the Registration Review process that 

ensures that all uses for that pesticide will be considered concurrently. The approach is outlined 

in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) – 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. 

In terms of volatilization, the Agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analyses are required for specific chemicals. 

Conclusions: The need for spray drift and volatilization risk assessment for fluometuron will be 

examined during Registration Review. 

7.0 Aggregate Risk Assessment 

In accordance with FQPA, HED must consider and aggregate (add) pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. The most recent 

aggregate risk assessment for currently registered uses of fluometuron was performed in 

conjunction with the 2005 Revised HED Risk Assessment for Phase III of the Reregistration 

Eligibility Decision (RED) (E. Reaves., 2/1/05, D341152). The Agency conducts aggregate 

exposure assessments by summing dietary (food and water) and residential exposures (residential 

or other non-occupational exposures). Since there are no registered/proposed uses of 

fluometuron that result in residential exposure, the chronic and cancer aggregate risk assessments 

are equal to the chronic and cancer dietary estimates (food and water only), respectively. Short-, 

intermediate-, and long-term aggregate-risk assessments were not performed because there are 

no registered or proposed uses of fluometuron that result in residential exposures. 

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Conclusions: As part of Registration Review, updated aggregate exposure and risk assessments 

are recommended. These assessments should reflect revised dietary exposure estimates and/or 

any revisions to the toxicological PODs. 

8.0 Occupational Exposure 

Fluometuron is registered for use on cotton. Attachment 4 provides a summary of the 

occupational use pattern. Fluometuron is currently registered as two technical formulations and 

four end use products formulated as a liquid with a maximum application rate of 2 lbs ai/acre. 

Additionally, fluometuron is registered for one SLN use on wildflowers at an application of 1 lbs 

ai/acre or 0.1 lbs ai/gallon. The HASPOC granted a data waiver for a subchronic inhalation 

study, with the provision that a respirator is used to protect workers when fluometuron is applied 

with a mechanically pressurized handgun to wildflowers in NC for the SLN use. Fluometuron 

applications can be made using aerial, ground, and handheld applications. 

Based on the registered use patterns, there is a potential for dermal and inhalation exposure to 

fluometuron in occupational scenarios from handling fluometuron products during the 

application process (i.e., mixer/loaders, applicators, and flaggers). The labels currently require 

mixer and loaders to wear baseline attire (i.e., long-sleeved shirt, long pants, socks, and shoes) 

along with coveralls and gloves for aerial applications. All other handlers must wear baseline 

attire with the addition of gloves, except applicators and flaggers. 

In addition, there is a potential for post-application worker exposure from entering into areas 

previously treated with fluometuron. The current restricted entry interval (REI) for postapplication activities is 24 hours. 

Occupational Handlers: In the 2005 risk assessment (E. Reaves, D341152, 2/5/2005) for 

fluometuron, an occupational handler assessment was conducted for the use on cotton at the 

maximum application rate of 2 lbs ai/acre. There were no non-cancer risk estimates of concern 

identified at that time at some level of risk mitigation. The cancer handler exposure and risk 

assessment was conducted at the average application rate of 1.5 lbs ai/acre. The days per year 

assumption (6 days for private applicators and 18 days for commercial applicators) were a 

deviation from the current policy. The handler cancer assessment for both dermal and inhalation 

cancer risks ranged from 2 x 10-6 to 2 x 10-4 at some level of risk mitigation. 

The 2005 risk assessment may not reflect the most up-to-date exposure data or inputs for 

occupational handlers. An updated occupational handler dermal and inhalation assessment may 

be conducted as part of Registration Review to reflect current ORE policies and updated 

toxicological PODs. The occupational exposure assessment should consider the provision that a 

respirator is used to protect workers when fluometuron is applied to wildflowers in NC (SLN 

use) with a mechanically pressurized handgun. 

Occupational Post-application: In the 2005 risk assessment for fluometuron, an occupational 

post-application assessment was conducted for post-application activities including irrigation, 

scouting, and hand weeding. No chemical-specific dislodgeable foliar residue data is available. 

Post-application risk estimates were not of concern (i.e., MOEs ≥100) on the day of treatment 

(i.e., Day 0) for all post-application exposure activities. The post-application cancer assessment 

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was conducted with the average application rate of 1.5 lbs ai/acre. The days per year assumption 

(6 days) is a deviation from the current policy. The 2005 assessment reported post-application 

risks for early season entry less than 1 x 10-6 on day 0, approximately 12 hours following 

application. The post-application cancer risks for later season entry are less than 1 x 10-4 on day 

0 and are less than 1 x 10-6 on day 12. 

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements 

(2007), one or more DFR studies are required when a pesticide has occupational uses that could 

result in post-application dermal exposure. Since the highest estimated occupational postapplication exposure using default DFR values for fluometuron is minimal in comparison to the 

level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of 

concern, MOE = 730 compared to the LOC of 100); EPA is waiving the 40CFR DFR data 

requirement. In this instance, it is unlikely that chemical-specific DFR data would be needed to 

further refine exposure assessments or would add appreciably to our overall understanding of the 

availability of dislodgeable foliar pesticide residues for fluometuron. Additional information is 

provided in Attachment 5. 

Conclusions: The occupational exposure database is adequate to support the Registration 

Review process for fluometuron. The most recent occupational handler and post-application 

exposure assessments may not be reflective of current exposure policies and data. During 

Registration Review, updated occupational handler dermal and inhalation assessments and a 

dermal post-application assessment may be conducted to reflect all currently registered uses and 

maximum application rates, current ORE policies, and/or updated toxicological PODs. 

Additionally, the SLN label (NC 120002) should be updated to indicate that a respirator is 

required when fluometuron is applied with a mechanically pressurized handgun.

9.0 Public Health and Pesticide Epidemiology Data 

The OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on the active ingredient fluometuron (Memo, E. Evans et al., 03/03/2016; 

D431967). The purpose of the database search is to identify potential patterns in the frequency 

and severity of the health effects attributed to fluometuron exposure. Fluometuron is not 

included in the Agricultural Health Study (AHS), and therefore this study does not provide 

information for this report. 

The OPP IDS records incidents in one of two modules: the Main IDS and the Aggregate IDS. 

The Main IDS contains incidents resulting in higher severity outcomes and provides more detail 

with regard to case specifics. The Aggregate IDS contains incidents resulting in less severe 

human incidents (minor, unknown, or no effects outcomes). For the Main IDS, from January 1, 

2010 to September 25, 2015, there were no incidents reported for fluometuron in the database. 

For the Aggregate IDS, from January 1, 2010 to September 25, 2015, there was one incident 

reported involving fluometuron. This incident was classified as minor severity. Overall, there 

are few incidents reported to IDS involving fluometuron. 

The SENSOR-Pesticides database covers 12 states from 1998-2011, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

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including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. A review of SENSORPesticides from 1998-2011 identifies no cases involving fluometuron. 

Conclusions: Based on the low frequency and severity of incident cases reported for 

fluometuron in both IDS and SENSOR-Pesticides there does not appear to be a concern at this 

time that would warrant further investigation. The Agency will continue to monitor the incident 

information and if a concern is triggered, additional analysis will be included in risk assessments 

for fluometuron. 

10.0 Tolerance Assessment and International Harmonization 

Fluometuron is registered for use on cotton and tolerances are established for residues of 

fluometuron in cotton and livestock commodities. Cereal grains, peanuts, rice, and soybeans are 

registered as rotational crops and inadvertent tolerances are also established for residues of 

fluometuron in these commodities. There are no Codex or Canadian MRLs established for 

residues of fluometuron; therefore, harmonization is not an issue at this time. The fluometuron 

International Residue Limit Status Sheet is available in Attachment 6. The tolerance expressions 

in 40 CFR§180.229 have not been updated to reflect current HED policies and will need to be 

revised during Registration Review. 

11.0 Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

most recent fluometuron human health risk assessment, in accordance with U.S. Executive Order 

12898, “Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populationsa

.” The OPP typically considers the highest potential exposures from the 

legal use of a pesticide when conducting human health risk assessments, including, but not 

limited to, people who obtain drinking water from sources near agricultural areas, the variability 

of diets within the U.S., and people who may be exposed when harvesting crops. Should these 

highest exposures indicate potential risks of concern, OPP further refines the risk assessments to 

ensure that the risk estimates are based on the best available information. 

12.0 Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to fluometuron and any other substances and fluometuron does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that fluometuron has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

 

a

 http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf 

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13.0 Human Studies 

Past fluometuron risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the 

Agricultural Handler Exposure Task Force (AHETF) Database, and the Agricultural Reentry 

Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies. 

14.0 Risk Assessment Updates and Data Deficiencies 

No toxicology or occupational/residential exposure data deficiencies were identified for 

fluometuron. Two required label updates and one residue chemistry deficiency have been 

identified for fluometuron and should be addressed as part of Registration Review: 

 The Flomet 4L label (EPA Reg. No. 66330-260) should be revised to remove the 

livestock gin trash feeding restriction since cotton gin trash is not under the control of the 

grower. 

 The SLN label (NC 120002) should be updated to indicate that a respirator is required 

when fluometuron is applied with a mechanically pressurized handgun. 

 Analytical reference standards should be submitted to EPA’s NPSR for the following 

fluometuron metabolites: trifluoromethylaniline (out of stock); CGA-236431 (expired on 

6/26/2014); CGA-236432 (expired on 6/26/2014); and CGA-13211 (expired on 

6/26/2014). See Attachment 9 for submission instructions. 

Additionally, EPA notes the following risk assessment updates may be needed during 

Registration Review: 

 Toxicology: 

o Re-evaluation of endpoints, doses, and safety factors to reflect current HED 

policies. 

 Residue Chemistry/Dietary Exposure: 

o Updated acute, chronic, and cancer dietary exposure and risk assessments that 

incorporate updated PCT data (including percent crop rotated data), monitoring data 

(if available), updated EDWCs from EFED, the most recent version of DEEMFCID, and any revised toxicological PODs. 

o Updated tolerance expressions in 40 CFR§180.229 to reflect current HED policies. 

 Occupational/Residential Exposure: 

o Spray drift and volatilization risk assessments to reflect current HED policies. 

o Updated occupational handler dermal and inhalation assessments and a dermal 

post-application assessment that reflect all currently registered uses, maximum 

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application rates, current ORE policies, and/or updated toxicological PODs 

 Aggregate Exposure: 

o Updated aggregate exposure analyses to reflect revised dietary exposure estimates 

and/or any revisions to the toxicological PODs. 

15.0 References

Memoranda Relevant to Registration Review. 

Author DP Barcode Date Title 

E. Reaves D341152 2/1/2005 Fluometuron: Revised HED Risk Assessment for Phase III 

of the Reregistration Eligibility Decision (RED). 

B. Smith D300551 12/7/2004 Fluometuron: Occupational Exposure Assessment for the 

Reregistration Eligibility Decision Document. 

S. Ary D300553 11/30/2004 

Fluometuron. Summary of Analytical Chemistry and 

Residue Data for the Reregistration Eligibility Decision 

(RED) Document. 

U. Habiba TXR No. 

0056795 9/25/2013 

Forchlorfenuron and Phenyl Urea Herbicides: Summary of 

Hazard and Science Policy Council (HASPOC) Meeting of 

September 12, 2013: Recommendations on the Data 

Requirement for an Immunotoxicity Study for 

Forchlorfenuron and for the Phenyl Urea Herbicides as a 

Class. 

S. 

Gallagher 

TXR No. 

0057314 02/16/2016 

Fluometuron: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of November 12, 2015: 

Recommendations on the Requirement for Subchronic 

Inhalation and Acute and Subchronic Neurotoxicity Studies. 

S. Ary D321682 9/27/2005 

Fluometuron. Revised Acute, Chronic, and Cancer Dietary 

Exposure Assessments for the Reregistration Eligibility 

Decision (RED) Document. 

S. Funk -- 2/22/1996 HED Metabolism Committee Memorandum 

P. Barnes D300532 4/23/2009 

Fluometuron. Review of data submitted by MakhteshimAgan of North America Inc. in response to the Health 

Effects Division (HED) data requirements and tolerance 

reassessment considerations included in the RED, Docket 

Number EPA-HQ-OPP-2004-0372 dated November 2005. 

(Federal Register: January 31, 2007 (Volume 72, Number 

20)) 

E. Evans 

et al. D431967 03/03/2016 Fluometuron: Tier I (Scoping) Review of Human Incidents and Epidemiology 

16.0 Attachments 

Attachment 1: Chemical Identity Tables. 

Attachment 2: Fluometuron Acute, Subchronic, and Chronic Toxicity Profile. 

Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (from 2005 

Risk Assessment). 

Attachment 4: Summary of Registered Uses for Fluometuron. 

Attachment 5: DFR Waiver Criteria. 

Attachment 6: Fluometuron International Residue Limit Status Sheet. 

Attachment 7. Bovine Liver and Milk Hydroxylated Metabolite Storage Stability Data. 

Attachment 8. Discussion of Chemistry Deficiencies Identified During Reregistration. 

Attachment 9. Submittal of Analytical Reference Standards (860.1650). 

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cc: J. Van Alstine (RAB6), S. Shelat (RAB6), N. McCarroll (RAB6) 

RDI: D. Davis (11/20/15), J. Rowland (11/24/15), J. Dawson (11/25/15) 

J. L.Van Alstine:S-10217:PY-S:(703)603-8866:7509P:RAB6

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Attachment 1: Chemical Identity Tables. 

Table A.1.1. Test Compound Nomenclature.

Chemical structure 

Common name Fluometuron 

Empirical formula C10H11F3N2O 

IUPAC name 1,1-dimethyl-3-(α,α,α-trifluoro-m-tolyl)urea 

CAS name N,N-dimethyl-N’-(3-(trifluoromethyl)phenyl)urea 

CAS number 2164-17-2 

PC Code 035503 

End-use products (EP) Cotton [66222-32; 66222-181; 66330-260; 83529-33; NC120002]; Wildflowers 

[NC 120002]

Table A.1.2. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value Reference 

Molecular weight 232.20 Merck Index 

pH Not available 

UV/visible absorption Not available 

Melting point/melting range 163-164.5C MRID 00019017 

Density 1.40 ± 0.02 g/cm3

 at 20C MRID 00019017 

Dissociation constant in water No dissociation MRID 42017302 

Octanol/water partition coefficient 242 (log P = 2.38) MRID 00160757 

Water solubility 105 ppm at 20C MRID 00152460 

Solvent solubility Acetone 15%, Chloroform 2%, Hexane less than 

4%, Methanol 14%, Methylene 2% at 20C 

MRID 00019017 

Vapor pressure 5 x 10-7 mm Hg at 20C MRID 00019017 

 

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Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name 

Chemical Name Chemical Structure 

Fluometuron 

1,1-dimethyl-3-(α,α,α-trifluoro-m-tolyl)urea 

CGA-41686 

1-methyl-3-(α,α,α-trifluoro-m-tolyl)urea 

CGA-41685 

1-(α,α,α-trifluoro-m-tolyl)urea 

Lysine Conjugate of CGA-41685 

Phospholipid Conjugate of CGA-41685 

CGA-13211 

1,1-dimethyl-3-(4-hydroxy-3-trifluoromethylphenyl)urea 

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Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name 

Chemical Name Chemical Structure 

CGA-236431 

1-(4-hydroxy-3-trifluoromethyl-phenyl)urea 

Sulfate Conjugate of CGA-236431 

CGA-236432 

1-methyl-3-(4-hydroxy-3-trifluoromethylphenyl)urea 

Sulfate Conjugate of CGA-236432 

CGA-72903 

Trifluoromethyl aniline (TFMA) 

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Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name 

Chemical Name Chemical Structure 

CGA-21835 

1-formyl-1-methyl-3-(α,α,α-trifluoro-mtolyl)urea 

N-demethylated CGA-21835 

1-formyl-3-(α,α,α-trifluoro-m-tolyl)urea 

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Attachment 2: Fluometuron Acute, Subchronic, and Chronic Toxicity Profile. 

A.2.1 Toxicology Data Requirements 

The requirements (CFR 158.340) for a food use for fluometuron are in Table A.2.1. Use of the 

new guideline numbers does not imply that new (1998) guideline protocols were used. 

Table A.2.1: Toxicology data requirements for a food use pesticide and whether or not they have been 

satisfied. 

Test 

Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity ...................................................... 

870.1200 Acute Dermal Toxicity ................................................. 

870.1300 Acute Inhalation Toxicity ............................................. 

870.2400 Primary Eye Irritation ................................................... 

870.2500 Primary Dermal Irritation ............................................. 

870.2600 Dermal Sensitization .................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) .............................................. 

870.3150 Oral Subchronic (nonrodent) ........................................ 

870.3200 21-Day Dermal ............................................................. 

870.3250 90-Day Dermal ............................................................. 

870.3465 90-Day Inhalation ......................................................... 

yes 

yes 

yes 

no 

yes 

yes 

yes 

yes 

no 

no1

870.3700a Developmental Toxicity (rodent) ................................. 

870.3700b Developmental Toxicity (nonrodent) ........................... 

870.3800 Reproduction ................................................................ 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) ............................................. 

8xicity 70.4100b Chronic Toxicity (nonrodent) ............................. 

870.4200a Oncogenicity (rat) ........................................................ 

870.4200b Oncogenicity (mouse) .................................................. 

870.4300 Chronic/Oncogenicity .................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes1

No

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial .................... 

870.5300 Mutagenicity—Gene Mutation - mammalian .............. 

870.5xxx Mutagenicity—Structural Chromosomal Aberrations .. 

870.5xxx Mutagenicity—Other Genotoxic Effects ...................... 

yes 

yes 

yes 

no 

yes 

yes 

yes 

no 

870.6100a Acute Delayed Neurotox. (hen) .................................... 

870.6100b 90-Day Neurotoxicity (hen) ......................................... 

870.6200a Acute Neurotox. Screening Battery (rat) ...................... 

870.6200b 90 Day Neuro. Screening Battery (rat) ......................... 

870.6300 Develop. Neuro ............................................................ 

no2 

no2

yes 

yes 

no 

- 

- 

no1 

no1 

no 

870.7485 General Metabolism ..................................................... 

870.7600 Dermal Penetration ....................................................... 

yes 

no 

yes 

no 

870.7800 Immunotoxicity (rat) yes no3

1

 Data waivers granted by HASPOC (U. Habiba, 2015; TXR No. 0057314) for subchronic inhalation study and for 

the acute and subchronic neurotoxicity studies. 

2

 Required only for organophosphate pesticides 

3

 Data waiver granted for immunotoxicity study (U. Habiba, 2013; TXR 0056795). 

 

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A.2.2 Toxicity Profiles 

The toxicology data for the acute toxicity studies with fluometuron (80 to 85% end use product)b are 

listed in Table A.2.2. The toxicity profile for fluometuron is presented in Table A.2.3. 

Table A.2.2: Acute Toxicity of Fluometuron.

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100 /Acute Oral (Rats) 40409302 

(1987) 

41216802 

 (1989) 

80% 

LD50 = 5223 mg/kg (M &F) 

85% 

LD50 = 3880 mg/kg (M) & >1000 

mg/kg (F) 

IV 

III 

870.1200 Acute Dermal (Rabbit) 40409303 

(1987) 

41216803 

(1989) 

80% 

LD50 = >2 g/kg (M& F) 

85% 

LD50 = 2020 mg/kg (M& F) 

III 

III 

870.1300 Acute Inhalation (Rat) 40409304 

(1987) 

41216804 

(1989) 

80% 

LC50 >0.6 mg/L 

85% 

LC50 >2.25 mg/L 

III 

IV 

870.2400 Primary Eye Irritation 

(Rabbit) 

40409305 

(1987) 

41216805 

(1989) 

80% 

Corneal opacity, iris irritation, 

chemosis, discharge cleared day 7 

in unwashed group; 72 hours in 

washed group 

85% 

Corneal opacity cleared day 4; 

conjunctival irritation cleared day 

10. 

II 

II 

870.2500 Primary Skin Irritation 

(Rabbit) 

40409306 

(1987) 

41216806 

(1989) 

80% 

Slight erythema 

85% 

Slightly irritating w/eschar, PIS = 

0.96 

II 

II 

870.2600 Dermal Sensitization 

(Guinea Pig) 

40409307 

(1987) 

41216807 

(1989) 

80% 

Non-sensitizing 

85% 

Non-sensitizing 

NA 

Table A.2.3. Toxicity Profile of Fluometuron 

Study Type MRID No. Results 

870. 3100 

90-day 

subchronicfeeding-rat

 

00019034 (1965) 

Acceptable/guideline 

0, 100, 1000 & 10,000 

ppm 

NOAEL = 8.2/7.8 mg/kg/day (100 ppm) 

LOAEL = 84/89 mg/kg/day, based on enlarged spleen and dark 

kidneys, which was more severe at the HDT. 

 

b

 End use product (80 or 85%) used for the acute studies 

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Table A.2.3. Toxicity Profile of Fluometuron 

Study Type MRID No. Results 

 (0, 8.2/7.8, 84/89 

&765/789 mg/kg/day 

(M&F) 

870. 3150 

13-week 

subchronicfeeding-dog 

00019035 (1965) 

Acceptable/guideline 

0, 40, 400 & 4000 ppm 

0, 1.5, 10 & 150 

mg/kg/day (M & F) 

NOAEL= 10 mg/kg (400 ppm) 

LOAEL = 150 mg/kg (4000 ppm), based on inflammatory 

reactions in the liver and kidney. 

870. 3200 

21-day dermal 

toxicity-rabbit 

00160763 (1964) 

Acceptable/guideline 

0, 10, 1000 & 1000 

mg/kg/day (M & F) 

NOAEL = 1000 mg/kg (HDT) 

No systemic or toxicity was seen at any dose tested. 

No LOAEL established. 

870.3465 

90-day 

Inhalation 

Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314). 

870. 4100 

ChronicFeeding-Dog 

40779001 (1988) 

41189501 (1988) 

Acceptable/guideline 

 0, 20, 400 & 7000 ppm 

(0, 0.6/0.7, 14/13 & 

237/237 mg/kg/day M/F 

NOAEL = 14/13 [M/F] mg/kg (400 ppm) 

LOAEL= 237 [M&F] mg/kg (7000 ppm), based on decreased 

body weight, food consumption, hemoglobin, hematocrit, 

RBC’s; increases in total bilirubin, Heinz & Howell-Jolly 

bodies, increased relative and absolute liver weight. 

870. 4200 

CarcinogenicityMouse 

00163845 (1986) 

42413501 (1992) 

43506601 (1994) 

Unacceptable 

0, 10, 500 & 2000 ppm 

(0, 1.2/1.4, 61.5/83.9 & 

260/265.8 mg/kg/day M 

& F) 

Study does not satisfy guideline requirement 83-2b for 

carcinogenicity testing in mice. 

NOAEL = 2000 ppm, the highest dose tested, based on the lack 

of any significant systemic toxicity. Significant increasing trend 

in alveolar/bronchiolar adenomas and/or carcinomas in males 

combined at p <0.05. Significant increasing trend and a pairwise comparison of the 2000 ppm group with controls for 

lymphocytic lymphomas at p < 0.05 in females. 

The RfD Committee considered the high dose to be inadequate 

for carcinogenicity testing; the HED Carcinogenicity Peer 

Review Committee (CPRC) concluded that the statistically 

significant increases in combined adenomas/carcinomas of the 

lungs in male mice and malignant lymphocytic lymphomas in 

female mice were observed at a dose that was less than adequate 

for fully assessing the carcinogenic potential of fluometuron 

(Taylor and Van Gemert, 1995; Spencer & Burnam, 1995); 

Taylor and Rinde, 1996)c

 

Based on these data, CPRC concluded that fluometuron 

should be classified as Group C (Possible Human 

Carcinogen) with a Q1* (mg/kg/day) of 1.80 x 10-1 in human 

equivalents (3/4’s scaling factor to convert from animal to 

humans) (Taylor and Rinde, 1996) 

 

c

 Taylor, L.L. and Van Germet, M. (1995). Toxicology Endpoint Selection Document, dated April 20, 1995. 

Spencer, H. W. and Burnam, W. (1995). Fluometuron: RfD/Peer Review Report, data July 20, 1995. Taylor, L.L. 

and Rinde, E. (1996). Carcinogenicity Peer Review of Fluometuron, dated August 28, 1996. TXR No. 0012049. 

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Table A.2.3. Toxicity Profile of Fluometuron 

Study Type MRID No. Results 

870. 4300 

Chronic 

toxicity/ 

Carcinogenicity 

-Rat 

 

00163772 (1982) 

Acceptable/guideline 

0, 10, 300 & 1000 ppm 

 (0, 0.55/0.69, 

17.17/21.20 & 

59.21/70.76 mg/kg/day 

M/F) 

NOAEL= 10 ppm (0.55/0.69 [M/F] mg/kg) 

LOAEL= 300 ppm (17.2/21.2 [M/F] mg/kg), based on 

hemosiderin deposition in the spleen. 

MTD= 1000 ppm based on reduced body weight gain. A 

histological re-examination resulted in statistically significant 

increases in pituitary adenomas in male rats at all doses; 

however, there was no significant trend, the response was flat. 

The RfD Committee considered the dose levels to be adequate 

[memo dated 12/09/93]. Satisfies guideline requirements (83-1a 

and 83-2a) for chronic toxicity/carcinogenicity testing in rats. 

No clear evidence of a carcinogenic effect in rats 

870.3700a 

Developmental 

Toxicity-Rat 

00163710 (1988)/ 

423897601 (1992) 

Acceptable/guideline 

0, 10, 100 & 1000 

mg/kg/day on GDs 6-15 

Maternal 

NOAEL= 10 mg/kg 

LOAEL= 100 mg/kg, based on the reduction of food 

consumption and on the increased darkened spleen. 

Developmental 

NOAEL= 10 mg/kg 

Developmental LOAEL= 100 mg/kg, based on an increased 

delayed urinary system development (shortened renal papillae). 

Females at 1000 mg/kg/day also exhibited: reduced body 

weight, reduced viability, lethargy & salivation. 

Fetal abnormalities at 1000 mg/kg/day included reduced fetal weig

increased resorptions & postimplantation loss, and skeletal 

abnormalities. 

870.3700b 

Developmental 

Toxicity-Rabbit 

00163774 (1986) 

00147554 (1984) 

42397602 (1992) 

Acceptable/guideline 

0, 1, 10 100 mg/kg/day 

on GDs 7-19 

Maternal 

NOAEL= 10 mg/kg 

LOAEL= 100 mg/kg, based on increased incidence of stool 

variations and abortions, reduced food consumption, decreased 

maternal body wt. gain. 

Developmental 

NOAEL= 100 mg/kg (HDT) No developmental toxicity was 

observed. 

870.3800 

Reproductive 

Toxicity 

Rat 2-generation 

00163773 (1982) 

Acceptable/nonguideline 

0, 10, 300 & 1000 ppm 

(0, 0.5, 15 & 50 

mg/kg/day 

M & F) 

Note: Study investigated 

3 generations 

Systemic (Parental) 

NOAEL= 0.5mg/kg (10 ppm) 

LOAEL= 15 mg/kg (300 ppm), based on spleen effects 

(extramedullary hematopoiesis, and an increase in hemosiderinladen macrophages). 

 

Reproductive 

 NOAEL= Study not rigorous enough to base a conclusion on 

whether Fluometuron has the potential to affect reproductive 

performance. 

RfD Committee concluded study is adequate for risk assessment

purposes. 

(TXR 010710)d

870.5100 

Gene Mutation – 

40802901 (1988) Negative for gene mutation in Salmonella strains TA100, TA98, 

TA1537, and TA1535 exposed up to 5000 μg/plate in repeat 

 

d

 Ghali, G. (1993). Fluometuron: RfD/Peer Review Report, dated December 9, 1993; TXR No. 010710. 

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Table A.2.3. Toxicity Profile of Fluometuron 

Study Type MRID No. Results 

Salmonella 

typhimurium

Acceptable/guideline assays +/- S9 

Mouse 

lymphoma 

45522002 (1988) EMS 

12 (1):85-154 

Negative up to lethal concentrations (1000 μg/mL –S9; 800 

μg/mL +S9) 

870.5395 

Micronucleus 

assay 

Chinese hamster 

bone marrow 

40882102 (1988) 

0, 1000, 2000 & 4000 

mg/kg 

Acceptable/guideline

Not clastogenic or aneugenic up to 4000 mg/kg 

870.5500 

Unscheduled 

DNA Synthesis 

Primary rat 

hepatocytes 

42017303 (1989) 

Acceptable/guideline

Fluometuron did not induce UDS in primary rat hepatocytes up 

to precipitating concentrations (≥ 537.5 μg/mL –S9). 

870. 6200a 

Acute 

neurotoxicity 

rats 

Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314). 

870.6200b 

90 Day 

neurotoxicity 

screening 

battery 

Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314). 

870.7485 

Metabolism-Rat 

40190702 (1986) 

Acceptable/guideline 

Single oral dose 0.5 & 

100 mg/kg radiolabeled 

or after preconditioning 

with 14 daily doses of 0.5 

mg/kg 

Single oral doses (0.5 & 100 mg/kg) of radiolabeled or to a 

single or dose (0.5 mg/kg) following a preconditioning period of 

14 daily 0.5 mg/kg doses of fluometuron were analyzed. 

Fluometuron is metabolized by oxidative processes to yield a 

variety of ring hydroxylated metabolites, which can be excreted 

directly or go on to further metabolism and/or conjugation prior 

to their ultimate excretion. Conjugated metabolites include betaglucuronides or aryl sulfates. This study can be assessed along 

with MRID 40047403 to describe the metabolism of 

Fluometuron. 

870.7485 

Metabolism-Rat 

40190702 (1986) 

Acceptable/guideline 

Single oral dose 0.5 & 

100 mg/kg radiolabeled 

or after preconditioning 

with 14 daily doses of 0.5 

mg/kg 

Following exposure to single oral doses (0.5 & 100 mg/kg) of 

radiolabeled fluometuron or to a single oral dose (0.5 mg/kg) 

following a preconditioning period of 14 daily 0.5 mg/kg doses, 

rats rapidly excreted the radio label, mainly in the urine, with 

the majority of that excreted in the urine occurring within the 

first 24 hrs following dosing. Urinary excretion was slightly 

dose-dependent, but no significant sex differences was 

observed. A small percentage (6-12%) of the dose was excreted 

in the feces. The highest concentration of radio label was 

associated with the red blood cells, with the well-perfused 

tissues displaying the next highest concentrations. Radio label 

was distributed to all tissues measured. The concentration of 

radiolabel remaining in the tissues at 168 hrs was dose-related 

and represented less than 0.2% of the administered dose. The 

overall recovery of radiolabel was approximately 90%. 

870.7800 

ImmunotoxicityFemale Rat 

Data waiver granted for immunotoxicity (Habiba, U, 2013; TXR No. 0056795). 

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Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (From 

2005 Risk Assessment).

Table A.3.1. Summary of Toxicological Doses and Endpoints for Fluometuron Human Health Risk Assessmentsa 

Exposure 

Scenario 

Point of Departure 

(POD) 

Uncertainty/ 

FQPA Safety 

Factors FQPA 

Safety Factor 

Level of Concern for 

Risk Assessment Endpoint for Risk 

Assessment 

Dietary Risk Assessments 

Acute Dietary 

females 13-49 

years

NOAEL= 10 mg/kg UFA=10x 

UFH=10x 

FQPA SF=1x 

Acute RfD = Acute 

PAD 

= 0.1 mg/kg/day 

MRID 00163710/42397601 

Acute- Developmental, Rat 

 LOAEL=100 mg/kg/day, based on delayed 

urinary system development.

Chronic 

Dietary 

all populations

NOAEL = 0.55 

mg/kg/day 

UFA=10x 

UFH=10x 

FQPA SF=1x 

Chronic RfD = Chronic 

PAD 

= 0.005 mg/kg/day

MRID 00163772 

Chronic-Chronic/Carcinogenicity, Rat 

LOAEL=17.2 mg/kg/day, based on 

increased splenic hemosiderin pigment 

deposition in both sexes.

Incidental Oral: No Residential Uses are Proposed for Fluometuron.

Dermal 

Exposure: 

Short-Term

Oral NOAEL= 10 

mg/kg/day 

(DAF=10%)b

UFA=10x 

UFH=10x 

FQPA SF=1x 

LOC for MOE=100 MRID 00163710/42397601 

Developmental, Rat 

LOAEL = 100 mg/kg/day, based on delayed 

urinary system development. 

Dermal 

Exposure:

IntermediateTerm

Oral NOAEL= 10 

mg/kg/day 

(DAF=10%)b

UFA=10x 

UFH=10x 

FQPA SF=1x 

LOC for MOE=100 MRID 00019035 

Subchronic, Dog

LOAEL=150 mg/kg/day, based on 

inflammatory reactions in the liver and 

kidney 

Dermal 

Exposure: 

Long-Term

No uses currently support a long-term dermal endpoint 

.

Inhalation 

Exposure: 

Short-Term

Oral NOAEL= 10 

mg/kg/day 

(IAF=100%)

UFA=10x 

UFH=10x 

FQPA SF=1x 

LOC for MOE=100 MRID 00163710/42397601 

Developmental, Rat

LOAEL = 100 mg/kg/day, based on delayed 

urinary system development. 

Inhalation 

Exposure: 

IntermediateTerm

Oral NOAEL= 10 

(IAF=100%)

UFA=10x 

UFH=10x 

FQPA SF=1x 

LOC for MOE=100 MRID 00019035 

Subchronic, Dog 

LOAEL =150 mg/kg/day, based on 

inflammatory reactions in the liver and 

kidney.

Inhalation 

Exposure: 

Long-term

No uses currently support a long-term inhalation endpoint.

Cancer Not mutagenic. Classified as Group C (Possible Human Carcinogen) with a Q1* (mg/kg/day)-1 of 1.80 x 10-2 in 

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Table A.3.1. Summary of Toxicological Doses and Endpoints for Fluometuron Human Health Risk Assessmentsa 

Exposure 

Scenario 

Point of Departure 

(POD) 

Uncertainty/ 

FQPA Safety 

Factors FQPA 

Safety Factor 

Level of Concern for 

Risk Assessment Endpoint for Risk 

Assessment 

human equivalents (3/4's scaling factor to convert from animals to humans).

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable. DAF = dermal absorption factor. IAF = inhalation absorption factor. 

a

 Data were extracted from Table 4, Toxicology Endpoints for Fluometuron, Reaves, E. and Nielson, A. Fluometuron: Revised 

HED Risk Assessment for Phase III of the Reregistration Eligibility Decision (RED). [PC Code 035503, DP Barcode 341152], 

dated February 1, 2005. 

bA 21-Day dermal toxicity study (MRID 00160763) exposed New Zealand White rabbits dermally at 0, 10, 100, or 1000 

mg/kg/day for 3 weeks and caused no systemic compound-related changes in males or female at any dose level [NOAEL = 1000 

mg/kg/day (HDT)]. Using the oral developmental rabbit study LOAEL of 100 mg/kg/day and the rabbit 21-day dermal study 

NOAEL (since no LOAEL established) of 1000 mg/kg/day, the estimated upper bound dermal absorption factor (DAF) is 10 

(100 mg/kg/day  1000 mg/kg/day).

 

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Attachment 4: Summary of Registered Uses for Fluometuron. 

Table A.4.1. Summary of Registered Uses for Fluometuron 

Use site/Crop 

[EPA Reg. No.]1

Application 

Equipment 

Maximum 

Application 

Rate (lb ai/A) 

Max rate per 

crop season 

(lb ai/A) 

Max # 

apps/crop 

season 

PHI 

(days) 

REI 

(hours) 

Cotton 

[66222-32; 66222-181; 66330-260; 

83529-33; NC120002] 

Ground 

Aerial 2 3 2 60 24 

Wildflowers 

[NC 120002] 

Ground 

Aerial 

Handheld 

1 

(0.1 lbs 

ai/gallon) 

NS NS NA 24 

NS=Not stated; NA=Not applicable. 

1

 EPA Reg No 11603-31 and 82633-19 are technical registrations.

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Attachment 5: DFR Waiver Criteria. 

In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, 

greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own 

farms, retail tree farms) uses that could result in post-application exposure to foliage. In the 

absence of chemical-specific DFR data, EPA uses default values. The 2012 Standard Operating 

Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of 

DFR studies, which resulted in the selection of a revised default values for the fraction of the 

application rate available for transfer after a foliar application (FAR). This value is based on an 

analysis of 19 DFR studies. Since that time, the Agricultural Re-entry Task Force has submitted 

information (MRID 49299201) that corrects an application rate error made in the original 

submission of “ARF039 – Determination of Dermal and Inhalation Exposure to Reentry Workers 

During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result of this 

submission, the default value of 25% was not changed as it still reflects a high-end, conservative 

value. However, it is important to note that the range of FAR values was revised from 2% - 89% 

to 2% - 47%. In the data, a large range of transferability is observed and this variability can 

potentially be attributable to many factors such as active ingredient; formulation; field conditions 

in the studies; weather conditions (e.g., humidity); or many other difficult to quantify 

factors. Although witnessed across multiple chemicals, this range in FAR values is not expected 

when considering DFR data for a single chemical. Because DFR data are not available for 

fluometuron, EPA is using the default value of 25%. Although there may be a small degree of 

uncertainty in the use of the default DFR value for fluometuron (i.e., there is a small chance that 

the FAR value may exceed the applicable default value), it is likely that the health-protective 

aspects of EPA’s occupational post-application assessment methodology will more than 

compensate for this potential uncertainty. For example, when assessing residential and 

occupational post-application exposure to gardens and ornamentals, EPA assumes the 

following: exposures occur to zero-day (i.e., day of application ) residues every day of the 

assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it 

doesn’t rain, etc); individuals perform the same post-application activities performed in the 

transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals 

engage in these post-application activities for a high-end amount of time every day (represented 

by data reflecting time spent gardening based on survey data). 

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. 

Since the highest estimated occupational post-application exposure using default DFR values for 

fluometuron is minimal in comparison to the level of concern (i.e., the calculated MOE is greater 

than 2 times higher than the level of concern, MOE = 730 compared to the LOC of 100); EPA is 

waiving the 40CFR DFR data requirement. In this instance, it is unlikely that chemical-specific 

DFR data would be needed to further refine exposure assessments or would add appreciably to 

our overall understanding of the availability of dislodgeable foliar pesticide residues for 

fluometuron. 

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for fluometuron at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for fluometuron. 

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Attachment 6: Fluometuron International Residue Limit Status Sheet. 

Fluometuron (PC Code 035503) 

Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition: 

US Canada Mexico1 Codex

40 CFR §180.229 

Primary Crops: fluometuron, N, N-dimethyl-N'-[3-

(trifluoromethyl)phenyl]urea, and its metabolite, 

trifluoromethylaniline (TFMA) determined as TFMA 

Livestock: fluometuron, N,N-dimethyl-N'-[3-

(trifluoromethyl)phenyl]urea, and its metabolites determined 

as TFMA and the hydroxylated metabolites: CGA-236431, 1-

(4-hydroxy-3-trifluoromethylphenyl)urea; CGA-236432, 1-

methyl-3-(4-hydroxy-3-trifluoromethylphenyl)urea; and 

CGA-13211, 1,1-dimethyl-3-(4-hydroxy-3-

trifluoromethylphenyl) urea 

None None 

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

US Canada Mexico1 Codex 

Primary Crops 

Cotton, gin byproducts 3.5 

Cotton, undelinted seed 1.0 

Livestock 

Cattle, meat byproducts 0.1 

Egg 0.1 

Goat, meat byproducts 0.1 

Hog, meat byproducts 0.1 

Horse, meat byproducts 0.1 

Milk 0.02 

Poultry, fat 0.1 

Poultry, meat 0.1 

Poultry, meat byproducts 0.1 

Sheep, meat byproducts 0.1 

Completed: M. Negussie; 10/30/15 

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

(d) Indirect or inadvertent residues. Tolerances are established for the 

combined residues of the herbicide fluometuron, N, N-dimethyl-N'-[3-

(trifluoromethyl)phenyl]urea, and its metabolite, 

trifluoromethylaniline (TFMA) determined as TFMA, in or on the 

following food commodities.Commodity 

Parts per million 

Grain, cereal, forage, fodder, and straw group 16, forage 3.0 

Grain, cereal, forage, fodder, and straw, group 16, stover 6.0 

Grain, cereal, group 15 0.5 

Peanut 0.1 

Peanut, hay 4.0 

Peanut, meal 0.2 

Soybean, forage 3.0 

Soybean, hay 3.0 

Soybean, seed 2.0 

Rice, hulls 1.0 

Wheat, milled byproducts 1.0 

 

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Attachment 7. Bovine Liver and Milk Hydroxylated Metabolite Storage Stability Data 

HED previously requested storage stability data for the hydroxylated metabolites of fluometuron 

(CGA-236431, CGA-236432, CGA-13211) in ruminant milk and muscle (up to 269 days) and 

egg and poultry tissues (approximately 4 months; Memo, S. Ary, 30-NOV-2004; D300553). 

Subsequently, the ChemSAC recommended that storage stability studies on the hydroxylated 

metabolites be conducted for residues in ruminant liver and milk samples and that any 

requirement for additional poultry data be deferred until the required ruminant storage stability 

data had been submitted and reviewed (ChemSAC Minutes, 17-OCT-2007). ChemSAC also 

recommended that if the ruminant storage stability data indicated that residues were stable, a 

poultry feeding study and storage stability data for egg and poultry tissues would not be required. 

Acceptable storage stability data for bovine liver and milk have been submitted to the Agency 

(MRID 48491201) and these deficiencies are now resolved. The results of the study showed that 

residues of the hydroxyfluometuron metabolites CGA-13211, CGA-235431, and CGA-235432 

are stable for at least 12.9 months for liver and 12.0 months for milk when stored at or below -12 

°C. Since the ruminant liver and milk data indicated that residues are stable for the storage 

duration, a poultry feeding study and storage stability data for egg and poultry tissues are not 

required at this time. The bovine liver and milk results are summarized below. 

Samples of bovine liver and milk were fortified with CGA-13211, CGA-236431, and CGA236432, at a level of 0.50 ppm for bovine liver and milk and put into storage at ~-12 °C. At 

intervals of 0, 1, 10, 12, and 13 months for liver and 0, 1, 3, 6, and 12 months for milk, stored 

samples and freshly fortified samples were analyzed for residues of CGA-13211, CGA-236431, 

and CGA-236432 using the enforcement method AG-678, a high performance liquid 

chromatography (HPLC) with fluorescence detection or liquid chromatography with mass 

spectrometric detection (LC/MS/MS) method. Method AG-678 was previously reviewed by the 

Agency (refer to 44623201.der; DP# 249612, 11/11/04, A. Nielsen). All bovine liver samples 

(except 0-day and 1-month) were analyzed by LC/MS/MS. All milk samples and 0-day and 1-

month liver samples were analyzed by HPLC with fluorescence detection. Acceptable 

concurrent recoveries were reported for bovine liver and milk samples at fortification levels of 

0.50 ppm, thus validating the method. The limit of quantitation (LOQ) was 0.02 ppm per analyte 

for bovine liver and 0.01 ppm per analyte for milk 

Table A.7.1. Stability of Hydroxyfluometuron Metabolite Residues in Bovine Liver and Milk During 

Storage at ~-12 °C. 

Commodity Storage Duration 

Days (Months) 

Fortification 

Level 

(ppm) 

Recovered Residues

(ppm) 

Mean 

Recovery 

(%) 

Mean 

Concurrent 

Recovery1 (%) 

Corrected 

Recovery2

(%) 

CGA-13211 

Liver 0 0.50 0.4413, 0.4408 88 88 -- 

35 (1.2) 0.3224, 0.3290 65 82 81 

316 (10.4) 0.2970, 0.3476 64 82 78 

365 (12.0) 0.4006, 0.2772 68 80 87 

392 (12.9) 0.3798, 0.4251 80 89 91 

Milk 0 0.50 0.5596, 0.5340 110 110 -- 

33 (1.1) 0.4654, 0.4792 94 57 198 

90 (3.0) 0.3836, 0.4549 84 96 89 

181 (6.0) 0.4029, 0.4212 82 82 100 

365 (12.0) 0.4321, 0.4905 92 93 100 

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Table A.7.1. Stability of Hydroxyfluometuron Metabolite Residues in Bovine Liver and Milk During 

Storage at ~-12 °C. 

Commodity Storage Duration 

Days (Months) 

Fortification 

Level 

(ppm) 

Recovered Residues

(ppm) 

Mean 

Recovery 

(%) 

Mean 

Concurrent 

Recovery1

 (%) 

Corrected 

Recovery2

(%) 

CGA-236431 

Liver 0 0.50 0.4166, 0.4562 87 87 -- 

35 (1.2) 0.3126, 0.3259 64 91 70 

316 (10.4) 0.3322, 0.3531 69 81 85 

365 (12.0) 0.3885, 0.2431 63 75 85 

392 (12.9) 0.3565, 0.4065 76 79 97 

Milk 0 0.50 0.5639, 0.4501 102 102 -- 

33 (1.1) 0.4173, 0.4358 85 53 179 

90 (3.0) 0.4000, 0.4694 87 93 93 

181 (6.0) 0.4127, 0.4207 83 85 98 

365 (12.0) 0.4664, 0.4781 94 95 99 

CGA-236432 

Liver 0 0.50 0.4037, 0.4358 84 84 -- 

35 (1.2) 0.2829, 0.3235 61 92 66 

316 (10.4) 0.3557, 0.3620 72 87 82 

365 (12.0) 0.3985, 0.2784 68 79 87 

392 (12.9) 0.3892, 0.4347 82 87 95 

Milk 0 0.50 0.5676, 0.4309 100 100 -- 

33 (1.1) 0.4226, 0.3992 82 50 186 

90 (3.0) 0.3809, 0.4372 82 88 93 

181 (6.0) 0.3846, 0.4153 80 84 95 

365 (12.0) 0.4687, 0.4863 96 95 101 1 Separate stored samples were not analyzed on Day 0. 2 Corrected for mean concurrent recovery. 

 

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Fluometuron Registration Review Human Health Assessment Scoping Document D430248 

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Attachment 8. Status of Chemistry Deficiencies Identified During Reregistration Several data requirements were identified as part of Reregistration (E. Reaves, 2/1/2005; D341152). Aside from the rerestriction from one label (EPA Reg. No. 66330-260), the chemistry data deficiencies identified as part of reregistration addressed. 

Table A.8.1. Status of Previously Identified Chemistry Data Deficiencies. 

Guideline Previously Identified Data Deficiencies1 Scoping Commen

860.1200 Directions for Use 

Label revisions are required for cotton and rotational crops. Cotton: The registrant must amend fluometuron labels with registered uses on cotton to reflect the test parameters for which adequate data are available. Product labels should be amended to specify: one preemergence treatment at a maximum rate of 2.0 lb ai/A, one early postemergence treatment at a maximum rate of 1.6 lb ai/A, and one layby treatment at a maximum rate of 2.0 lb ai/A. A maximum seasonal rate of 5.6 lb ai/A should be established. 

The use patterns are summarized The maximum use seasonal use rall labels, which is lower than the 5.6 lb ai/A that was indicated in tcurrent labels indicate that the maof applications per year is 2. The preplant, preemergence, and postapplication instructions that are bThe treatments rates are equivalethe rates indicated in the RED for timing of application. Label reviapplication rate and number of aprequired at this time. 

In addition, because cotton gin trash is a livestock feed item not under control of the grower, the feeding restriction must be removed from the product labels. 

The Flomet 4L label (EPA Reg. Nstill contains a gin trash livestock restriction that should be remove

Rotational Crops: Label amendments for all fluometuron end-use products are required to specify the appropriate plantback intervals for rotational crops. Adequate data are available to support the following intervals: three months for wheat; eight months for field corn, sweet corn, and peanuts; and nine months for rice, grain sorghum, and soybeans. 

The appropriate plantback intervathe registered labels. If the registsupport rotational crops and planother than those listed, then additcrop field trials must be conducte

860.1340 Residue Analytical Method - Animal Commodities 

The registrant must either improve Method AG-519A or develop a new method capable of determining fluometuron residues that may be converted to TFMA in livestock commodities. The proposed enforcement method should undergo an independent laboratory validation according to PR Notice 96-1 dated 2/7/1996. Once a successful 

independent laboratory validation has been completed, the proposed method will be subject to a method trial by the Agency. 

The Registrant submitted a waiverevised Method AG-519A, and Hsupporting rationale and recommstudy requirement be waived (Me23-APR-2009; D300532). The Amethod data (without laboratory Methods 519, 519A, AG-678, AG529 and concluded that the methomeet the 860.1340 Residue Chem
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Table A.8.1. Status of Previously Identified Chemistry Data Deficiencies. 

Guideline Previously Identified Data Deficiencies1 Scoping Commen

Guidelines for acceptable toleranmethods (Memo, C. Stafford, 13-D300532). 

860.1380 Storage Stability Data 

Samples of cottonseed and cotton gin byproducts that are to be collected from the required field trials should be stored under frozen storage conditions and analyzed within the storage interval for which residues of fluometuron, determined as TFMA, have been found to be stable (ca. twenty months). 

The cottonseed and cotton gin byno longer required because the Dhave been cancelled. 

Fluometuron was stable in beef muscle and in liver stored frozen for two years. Fluometuron was stable in milk stored frozen for up to one year. Additional data are required on the stability of the hydroxylated metabolites (CGA-236431, CGA-236432, CGA-13211) in milk and muscle. The storage intervals and conditions must be approximate to those of the ruminant feeding study. 

Acceptable storage stability data and milk have been submitted (Mand these deficiencies are now re13211, CGA-235431, and CGA-2for at least 12.9 months for liver for milk when stored at or below 

The egg and poultry tissue samples from an existing poultry feeding study were stored frozen for ca. four months. A study must be conducted investigating the stability of the hydroxylated metabolites (CGA-236431, CGA-436432, CGA-13211, and their conjugates) following storage under the same storage conditions and for the same interval. 

Since the ruminant liver and milk that residues are stable for the stopoultry feeding study and storage egg and poultry tissues are not re(ChemSAC Minutes, 17-OCT-20

860.1500 Crop Field Trials Cottonseed and gin byproducts 

Additional data depicting residues of fluometuron and its metabolites determined as TFMA and the hydroxylated metabolites in/on cottonseed are required. Cottonseed should be harvested/collected at normal maturity following applications of the DF formulation according to the following treatment schedule: one preemergence application at 2.0 lb ai/A, one early postemergence foliar application (when plants are 3-6 in high) at 1.6 lb ai/A, and one layby foliar application at 2.0 lb ai/A. A minimum of six trials must be conducted. The cotton plants must be harvested by commercial equipment (or similar thereof) to provide an adequate representation of plant residue from the ginning process. Stripper harvesting should be used for three trials and mechanical picker harvesting should be used for three trials. The six trials should represent the principal U.S. growing regions. 

The DF formulations have been ctherefore, these data are no longedata may be required in the futurreceives petitions for the use of D

860.1900 Field Rotational Crops 

Rotational Crops: Label amendments for all fluometuron end-use products are required to specify the appropriate plantback intervals for rotational crops. Adequate data are available to support the following intervals: three months for wheat; eight months for field corn, sweet corn, and peanuts; and nine months for rice, grain sorghum, and soybeans. 

The registered labels reflect the pthat are supported by the rotationthe registrant wishes to support roand plantback intervals other than above, then additional rotational must be conducted. 1 Data needs were identified in Table 6 of Memo, E. Reaves, 01-FEB-2005; D341152.
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Attachment 9. Submittal of Analytical Reference Standards (860.1650) 

Analytical reference standards for parent fluometuron are currently available in EPA’s National 

Pesticide Standards Repository (NPSR) and expire on 6/30/2016. Analytical reference standards 

are currently unavailable in EPA’s NPSR for the following metabolites: trifluoromethylaniline 

(out of stock); CGA-236431 (expired on 6/26/2014); CGA-236432 (expired on 6/26/2014); and 

CGA-13211 (expired on 6/26/2014) (Email communication with G. Verdin of BEAD/ACB on 

11/9/2015). The registrant is required to maintain reasonable amounts of the reference standards 

for fluometuron and its metabolites in the NPSR as long as tolerances remain published in 

40CFR §180.229. When necessary, new reference standards, or updated certificates of analysis 

(COAs), should be sent to the ACB, which is located at Fort Meade, MD. It should be sent to the 

attention of either Theresa Cole or Thuy Nguyen at the address listed below, along with a letter 

of transmittal. Please note that the full 9-digit ZIP Code is required, or the mail will be 

returned to the registrant. 

 USEPA 

 National Pesticide Standards Repository 

 Analytical Chemistry Branch/BEAD/OPP 

 701 Mapes Road 

 Fort George G. Meade, MD 20755-5350 

The letter of transmittal should include the assay of the standard, name of the analytical method 

used, a statement of principal impurities, purification procedures employed, storage 

requirements, and special precautions for safe handling. Replacement of standards, or updated 

COAs, may be required periodically if supplies are exhausted, if the standards expire, or if 

decomposition occurs during storage. Material Safety Data Sheets (MSDSs) must accompany all 

analytical standards as specified by the Occupational Safety and Health Administration (OSHA) 

in 29CFR §1910.1200. 

Page 33 of 39
Fluometuron [PC Code 035503]/ Makhteshim-Agan of North America 

B.7.8.3 Stability of Residues Prior to Analysis 

B.7.8.3 Bovine Liver and Milk 

Document ID: 

Report: 

Guidelines: 

GLP Compliance: 

Acceptability: 

Evaluator: 

MRID No. 48491201 

Barker, W. (2011) Determination of Hydroxyfluometuron Metabolites 

Stability in Frozen Liver and Milk. Study ID#: 09-0036. Unpublished 

study prepared by Makhteshim-Agan of North America, Inc. 178 p. 

EPA OCSPP Harmonized Test Guideline 860 .13 80 Storage Stability Data 

(August 1996) 

PMRA Regulatory Directive DIR98-02 - Residue Chemistry Guidelines, 

Section 5 - Storage Stability Data 

OECD Guideline 506 Stability of Pesticide Residues in Stored 

Commodities (October 2007) 

No deviations from regulatory requirements were reported which would 

have an impact on the validity of the study. 

The study is considered scientifically acceptable. The acceptability of this 

study for regulatory purposes is addressed in the U.S. EPA Human Health 

Scoping Document (D430248; D391415). 1 , /' 11 

Julie L. Van Alstine, MPH, Environmental Health Scientist , _Jt.1} ..1-,,_, V w..... ./r'-------

Risk Assessment Branch 6 (RAB 6)/Health Effects Division (HED) 

Note: This Data Evaluation Record (DER) was originally prepared under contract by Versar, Inc. (6850 Versar Center, 

Springfield, VA 22151; submitted 8/5115). The DER has been reviewed by HED and revised to reflect current Office of 

Pesticide Programs (OPP) policies. 

EXECUTIVE SUMMARY 

Makhteshim-Agan of North America, Inc. has submitted the results of a storage stability study of 

the hydroxyfluometuron metabolites CGA-13211, CGA-236431, and CGA-236432 in bovine 

liver and milk. Samples of bovine liver and milk were fortified with CGA-13211 , CGA-236431, 

and CGA-236432, at a level of 0.50 ppm for bovine liver and milk and put into storage at ~-12 

°C. At intervals of 0, 1, 10, 12, and 13 months for liver and 0, 1, 3, 6, and 12 months for milk, 

stored samples and freshly fortified samples were analyzed for residues of CGA-13211, CGA236431, and CGA-236432. 

At each storage interval, hydroxyfluometuron metabolites, CGA-13211, CGA-236431, and 

CGA-236432, were determined using Method AG-678, a high performance liquid 

chromatography (HPLC) with fluorescence detection or liquid chromatography with mass 

spectrometric detection (LC/MS/MS) method to determine residues of CGA-13211, CGA236431 , and CGA-236432. Acceptable concurrent recoveries were reported for bovine liver and 

milk samples at fortification levels of 0.50 ppm, thus validating the method. The limit of 

quantitation (LOQ) was 0.02 ppm per analyte for bovine liver and 0.01 ppm per analyte for milk. 

Under these conditions, residues ofhydroxyfluometuron metabolites, CGA-13211, CGA236431, and CGA-236432, were stable in bovine liver at 12.9 months and milk at 12.0 months. 

EPA MRID #: 48491201 

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I. MATERIALS AND METHODS 

A. MATERIALS 

1. Test Material 

Table B.7.8.3-1. Nomenclature for Fluometuron and Metabolites of Interest.

Common name Fluometuron 

Identity N,N-dimethyl-N’-(3-(trifluoromethyl)phenyl)urea 

CAS no. 2164-17-2 

Company experimental name Not applicable 

Other synonyms (if applicable) Not applicable 

Metabolite CGA-13211 

Identity 1,1-dimethyl-3-(α,α,α-trifluoromethyl-4-hydroxy-m-tolyl)urea 

CAS no. Not available 

Company experimental name ET-2613 

Other synonyms (if applicable) Not applicable 

Metabolite CGA-236431 

Identity (α,α,α-trifluoromethyl-4-hydroxy-m-tolyl)urea 

CAS no. Not applicable 

Company experimental name ET-2614 

Other synonyms (if applicable) Not applicable 

Metabolite CGA-236432 

Identity 1-methyl-3-(α,α,α-trifluoromethyl-4-hydroxy-m-tolyl)urea 

CAS no. Not applicable 

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Table B.7.8.3-1. Nomenclature for Fluometuron and Metabolites of Interest.

Company experimental name ET-2612 

Other synonyms (if applicable) Not applicable 

2. Test Commodity 

Livestock Matrix: Bovine liver and milk. 

B. STUDY DESIGN 

1. Test Procedure 

The stock solutions of CGA-13211, CGA-236431, and CGA-236432 (1000 μg/mL) were diluted 

with methanol and stored frozen. Untreated samples of bovine liver and whole milk were 

acquired from a grocery store. Liver samples were ground in a Hobart food processor and whole 

milk was thoroughly shaken before fortification with CGA-13211, CGA-236431, and CGA236432. 

A total of 33 sub-samples of each of the two different matrices were weighed into polyethylene 

bottles. For each matrix, 4 sub-samples were used as control samples and procedural recovery 

samples. The remaining 2 sub-samples were fortified with each analyte individually at 0.50 ppm 

and were to be used for storage stability samples. 

On the day of sample fortification (0 day), a single control and duplicate samples fortified with 

0.50 ppm of CGA-13211, CGA-236431, and CGA-236432 were analyzed. The remaining 

samples were transferred to freezer storage (-12 °C) until required for analysis. Liver samples 

were analyzed after storage intervals of approximately 0, 1, 3, and 12 months (with a 10 and 13 

month added); actual storage periods were 0 days (0 months), 35 days (1.2 months), 316 days 

(10.4 months), 365 days (12.0 months), and 392 days (12.9 months). Milk samples were 

analyzed after storage intervals of approximately 0, 1, 3, 6, and 12 months; actual storage periods 

were 0 days (0 months), 33 days (1.1 months), 90 days (3.0 months), 181 days (6.0 months), and 

365 days (12.0 months). At the specified storage interval, a set of samples for each livestock 

matrix was removed from frozen storage for analysis. The sample set for each storage interval 

consisted of the same number of samples as the sample set from the day-0 analysis. No 

concurrent recovery samples were run for the day-0 sampling set. 

2. Description of Analytical Procedures 

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Samples of bovine liver and milk were analyzed for residues of CGA-13211, CGA-236431, and 

CGA-236432 using the proposed enforcement method, AG-678, that was previously reviewed by 

the Agency (refer to 44623201.der; DP# 249612, 11/11/04, A. Nielsen). A complete description 

of the method was included in the submission. All bovine liver samples (except 0-day and 1-

month) were analyzed by LC/MS/MS. All milk samples and 0-day and 1-month liver samples 

were analyzed by HPLC with fluorescence detection. 

For bovine liver, samples were refluxed with methanol (MeOH):5% acetic acid (80:20; v:v). 

Following filtration, an aliquot of the extract was evaporated to the remove the organic solvent 

and diluted with water. The aqueous solution is then hydrolyzed with enzymes (β-glucuronidase 

and sulfatase) and cleaned up on a C18 solid phase extraction (SPE) column, if necessary (HPLC 

analysis with fluorescence detection only). Residues were eluted with MeOH:0.1% acetic acid 

(60:40, v:v). The eluate was evaporated to dryness and partitioned into ethyl acetate:hexane 

(80:20, v:v). The extracts were cleaned up on a C18 SPE column (HPLC analysis with 

fluorescence detection only). Residues were eluted with ethyl acetate:MeOH:acetonitrile (ACN) 

(270:20:10; v:v:v). The eluate was evaporated near dryness, redissolved in a mixture of acetic 

acid (0.1%):MeOH (70:30, v:v) to yield the final fraction. An aliquot of the final fraction was 

injected into an HPLC system for quantitation of residues by fluorescence detection (0-day and 

1-month liver samples only) or LC/MS/MS (all liver samples, except 0-day and 1-month). 

For bovine milk, samples were extracted with methanol. Following filtration, an aliquot of the 

extract was evaporated to the remove the organic solvent and diluted with water. The aqueous 

solution was then hydrolyzed with enzymes (β-glucuronidase and sulfatase), partitioned into 

ethyl acetate:hexane (80:20, v:v), and cleaned up on a C18 solid phase extraction (SPE) column. 

Residues were eluted with ethyl acetate:MeOH:ACN (270:20:10, v:v:v). The eluate was 

evaporated near dryness, redissolved in a mixture of acetic acid (0.1%):MeOH (70:30, v:v) to 

yield the final fraction. An aliquot of the final fraction was injected into an HPLC system for 

quantitation of residues by fluorescence detection. 

For LC/MS/MS, the following ion transitions were monitored for quantitation: m/z 219 → 156 

for CGA-13211, m/z 247 → 183 for CGA-236431, and m/z 233 → 156 for CGA-236432. The 

reported LOQs for each analyte were 0.02 ppm for liver and 0.01 ppm for milk. 

II. RESULTS AND DISCUSSION 

Method performance was evaluated by use of concurrent recovery samples by fortification 

bovine liver and milk at 0.50 ppm. All recoveries were generally within the acceptable range of 

70-120%; therefore, the method was considered valid for the analysis of hydroxyfluometuron 

and metabolite residues in bovine matrices (Table B.7.8.3-2). Concurrent recoveries were used 

to correct the residues in the stored samples. 

The detector response was linear (coefficient of determination, r2 ≥0.9849 for CGA-13211, r2

≥0.9984 for CGA-236431, and r2 ≥0.9866 for CGA-236432 within the range of 0.01-0.50 

μg/mL). Representative chromatograms of control samples, fortified samples, and treated 

samples were provided. The control chromatograms generally had no peaks of interest above the 

chromatographic background. Residues in controls were below the LOQ (≤0.02 ppm) for liver 

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and below the LOQ (≤0.01 ppm) for milk with the exception of one untreated milk sample at 33 

days bore detectable residues of CGA-236431 at 0.0142 ppm. 

Table B.7.8.3-2. Summary of Procedural/Concurrent Recoveries of Hydroxyfluometuron Metabolites, 

CGA-13211, CGA-236431, and CGA-236432 from Bovine Liver and Milk. 

Matrix Fortification Level 

(ppm) 

Storage Interval 

(days) 

Sample size

(n) 

Recoveries1 (%) Mean ± Std. Dev.2

(%) 

CGA-13211 

Liver 0.50 0 2 88, 88 88 

35 2 94, 70 82 

316 2 79, 85 82 

365 2 74, 85 80 

392 2 95, 84 90 

Milk 0.50 0 2 112, 107 110 

33 2 34, 79 57 

90 2 104, 88 96 

1813 2 78, 87 83 

365 2 88, 97 93 

CGA-236431 

Liver 0.50 0 2 83, 91 87 

35 2 92, 91 92 

316 2 81, 81 81 

365 2 71, 79 75 

392 2 85, 74 80 

Milk 0.50 0 2 113, 90 102 

33 2 36, 69 53 

90 2 91, 95 93 

1813 2 81, 90 86 

365 2 90, 101 96 

CGA-236432 

Liver 0.50 0 2 81, 87 84 

35 2 94, 91 93 

316 2 87, 87 87 

365 2 73, 85 79 

392 2 92, 82 87 

Milk 0.50 0 2 114, 86 100 

33 2 34, 65 50 

90 2 87, 89 88 

1813 2 79, 89 84 

365 2 89, 101 95 1

 Concurrent recoveries were corrected for apparent residues in controls. 

2 Standard deviation is not calculated for sample sizes <3. 3 The fresh fortification and stored fortification recoveries reported for two samples of milk from the 181-day storage interval in 

the summary tables (p. 10 & 19) in the submission were reversed. These values are the recoveries found in the raw data on p. 

154-155.

The results of the storage stability study are presented in Table B.7.8.3-3. The results of the 

study showed that residues of hydroxyfluometuron metabolites, CGA-13211, CGA-235431, and 

CGA-235432, are stable for at least 12.9 months for liver and 12.0 months for milk when stored 

at or below -12 °C. 

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Table B.7.8.3-3. Stability of Hydroxyfluometuron Metabolite Residues in Bovine Liver and Milk During 

Storage at ~-12 °C. 

Commodity Storage Duration 

Days (Months) 

Fortification 

Level 

(ppm) 

Recovered Residues

(ppm) 

Mean 

Recovery 

(%) 

Mean 

Concurrent 

Recovery1 (%) 

Corrected 

Recovery2

(%) 

CGA-13211 

Liver 0 0.50 0.4413, 0.4408 88 88 -- 

35 (1.2) 0.3224, 0.3290 65 82 81 

316 (10.4) 0.2970, 0.3476 64 82 78 

365 (12.0) 0.4006, 0.2772 68 80 87 

392 (12.9) 0.3798, 0.4251 80 89 91 

Milk 0 0.50 0.5596, 0.5340 110 110 -- 

33 (1.1) 0.4654, 0.4792 94 57 198 

90 (3.0) 0.3836, 0.4549 84 96 89 

181 (6.0) 0.4029, 0.4212 82 82 100 

365 (12.0) 0.4321, 0.4905 92 93 100 

CGA-236431 

Liver 0 0.50 0.4166, 0.4562 87 87 -- 

35 (1.2) 0.3126, 0.3259 64 91 70 

316 (10.4) 0.3322, 0.3531 69 81 85 

365 (12.0) 0.3885, 0.2431 63 75 85 

392 (12.9) 0.3565, 0.4065 76 79 97 

Milk 0 0.50 0.5639, 0.4501 102 102 -- 

33 (1.1) 0.4173, 0.4358 85 53 179 

90 (3.0) 0.4000, 0.4694 87 93 93 

181 (6.0) 0.4127, 0.4207 83 85 98 

365 (12.0) 0.4664, 0.4781 94 95 99 

CGA-236432 

Liver 0 0.50 0.4037, 0.4358 84 84 -- 

35 (1.2) 0.2829, 0.3235 61 92 66 

316 (10.4) 0.3557, 0.3620 72 87 82 

365 (12.0) 0.3985, 0.2784 68 79 87 

392 (12.9) 0.3892, 0.4347 82 87 95 

Milk 0 0.50 0.5676, 0.4309 100 100 -- 

33 (1.1) 0.4226, 0.3992 82 50 186 

90 (3.0) 0.3809, 0.4372 82 88 93 

181 (6.0) 0.3846, 0.4153 80 84 95 

365 (12.0) 0.4687, 0.4863 96 95 101 1 Separate stored samples were not analyzed on Day 0. 2 Corrected for mean concurrent recovery. 

III. CONCLUSIONS 

The storage stability study with bovine liver and milk is considered scientifically acceptable. 

The results of the study showed that residues of hydroxyfluometuron metabolites CGA-13211, 

CGA-235431, and CGA-235432, are stable for at least 12.9 months for liver and 12.0 months for 

milk when stored at or below -12 °C. 

REFERENCES

44623201.der; DP# 249612, 11/11/04, A. Nielsen 

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